Sex and age disparities in the influence of tobacco smoking on depression: Evidence from the Taiwan Biobank

INTRODUCTION The global tobacco epidemic poses a notable challenge to global health due to its association with various tobacco-related diseases. Although tobacco smoking is associated with depression, the exact mechanism by which tobacco smoking increases the risk of depression is unclear. This study explored the potential effects of tobacco smoking on depression. METHODS We used data in the analysis from the Taiwan Biobank of 27916 individuals recruited from 2015 to 2020. To investigate the associations between tobacco use and depression, the results of the depression-measuring subscale of the Patient Health Questionnaire-4 as well as data on participants’ tobacco consumption and other relevant covariates, were analyzed. RESULTS Participants who smoked were more likely to report depression than those who did not smoke (AOR=1.50; 95% CI: 1.21–1.86). Furthermore, depression was significantly higher in women who smoked than in their male counterparts (females: AOR=1.68; 95% CI: 1.27–2.23, and males: AOR=1.32; 95% CI: 0.96–1.80). Women aged <55 years and who smoked were more likely to report depression, whereas this trend was not observed in those aged ≥55 years (<55 years: AOR=1.75; 95% CI: 1.23–2.48), and ≥55 years: AOR=1.58; 95% CI: 0.97–2.56). CONCLUSIONS Tobacco smoking is a significant factor associated with depression, particularly in younger women. The increasing prevalence of tobacco use for years among younger women in Taiwan might contribute to shifts in the associations between depression and tobacco use in women.


INTRODUCTION
The global tobacco epidemic poses a notable challenge to global health, as evidenced by its association with various tobacco-related diseases 1 .Tobacco smoking is associated with an increased risk of mental illness 2 .Depression is one of the most prevalent mental ailments worldwide, and it has imposed an increasing economic burden in recent years 3 .Between 2010 and 2018, the population of adults in the United States with major depressive disorder (MDD) increased by 12.9%.Notably, the economic burden associated with the increased prevalence of MDD in the adult population increased by 37.9% 4 .The impact of depression encompasses not only its symptomatic aspects but also the impairment of occupational or educational functioning caused by the disorder and the care burden of family and friends.Although the relationship between depression and tobacco use has been demonstrated, the precise influence of tobacco use on depression is not well understood 5 .Tobacco use can increase the risk of depression or lead to the further use of tobacco as self-medication to combat depression.The shift in tobacco consumption trends in recent years is noteworthy, with smoking becoming increasingly prevalent among women, especially younger women 6 .Consequently, understanding the factors contributing to both tobacco smoking and depression is imperative.In addition to tobacco smoking, alcohol, coffee, and tea are commonly consumed, and the possible connections with substance use disorder have been noted [7][8][9][10] .
Numerous studies have investigated various risk factors for depression, and their results revealed that the risk of depression is influenced by an interplay of complex factors such as age, sex, body mass index (BMI), sleep, physical exercise, education level, residential area, and family history.Aging has been demonstrated to cause a modest increase in depressive symptoms in both men and women 11 .In terms of sex, women have been reported to have a higher prevalence of depression than men; however, the results have been inconsistent 12 .A higher BMI is associated with a higher risk of depression 13 .The sleep pattern has been a suspected contributor to depression 14 , with emerging interest in aspects beyond the total sleep time and sleep quality.The concept of social jet lag (SJL), which refers to the differences in sleep patterns between weekdays and weekends, was found to be related to psychiatric disorders, including depression 15 .Regular physical exercise has attracted attention for its potential preventive or therapeutic effects against depression 16 .Additionally, a higher education level has been demonstrated to exert a protective effect against depression, but this relationship remains underexplored 17 .Furthermore, a family history of depression has been recognized as a risk factor for depression onset and severity 18 .
This study explored the potential impact of tobacco smoking on depression.Our research was conducted using the extensive data available in the Taiwan Biobank (TWB), and the data aided in the identification of influence between tobacco smoking and depression.

METHODS
We conducted a population-based, pooled, crosssectional study using information on 33741 participants joining the TWB database during the years 2015 through 2020.To protect the participants' confidentiality, de-identified data were received and used without alteration.The TWB has been established as a government-supported initiative aimed at obtaining lifestyle and genetic data from the Taiwanese population 19,20 .The recruitment process for the TWB involves enlisting community-based volunteers aged 30-70 years who have no history of cancer.After providing written informed consent, individuals participating in the TWB provided information pertaining to their daily lives, provided blood samples, and underwent a physical examination.In addition to blood sample collection and physical examination, each participant was required to complete a questionnaire through a face-to-face interview with one of the TWB researchers.The questions were related to personal information and lifestyle factors.

Depression measurement
In the TWB, depression tendencies were assessed using the Patient Health Questionnaire-4 (PHQ-4) 19 .PHQ-4 is a short self-report 4-item questionnaire that contains two subscales including a 2-item anxiety scale (GAD-2) with the first two questions and a 2-item depression scale (PHQ-2) with the last two questions.A total score of ≥3 for the last two questions of the questionnaire indicated the presence of depression.This established criterion was employed in our study for evaluating depression 20 .

Tobacco smoking
The study also conducted a survey of tobacco smoking which was divided into non-smoking and smoking groups.Smoking was defined as regularly engaging in smoking for a minimum duration of 6 months and not quitting smoking prior to completing the PHQ-4 questionnaire.

Covariates in this study
During the interview for the TWB, a range of demographic data were collected including sex (male vs female); age (≥55 vs <55 years); BMI (≥25 vs <25 kg/m 2 ); regular exercise (yes vs no); education level (college or graduate school vs high school, elementary school, or none); alcohol, coffee, and tea consumption (yes vs no); sleep patterns such as total sleep duration on weekdays compared to weekend, sleep differences between weekdays and weekend, and sleep quality; and family history of mental illness.For sleep quality data, the original categories of very good, good, average, bad, and very bad were dichotomized into: Good + (very good, good, and average) and Bad + (bad and very bad).During the interview for the TWB, the BMI (kg/m 2 ) was measured 2 .These data were considered covariates for subsequent analyses according to the methods described in previous studies 7,[12][13][14][15][16][17][18]21 .
We also recorded the occurrence of menopause among women who were part of the TWB and were aged >40 years.

Statistical analysis
Characteristics of participants, with and without tobacco smoking behaviors, are expressed using means and standard deviation for continuous data, frequencies and percentages for categorical data, and odds ratios (ORs) with 95% confidence intervals.Continuous variables were compared using Student's t-test, and categorical data were compared using the χ 2 test or Fisher's exact test.Participant characteristics with a p<0.05 were included in the logistic regression model, which was used to estimate covariate-adjusted odds ratios (AORs) for the possible association with depression.We analyzed all data using the Windows version 9.4 of SAS (Statistical Analysis System) (SAS Institute Inc.; Cary, NC).A p<0.05 was considered statistically significant.

Basic characteristics of TWB participants
After excluding 3201 participants aged <40 years

Associations between tobacco use and depression across age groups in females
To further refine the analysis, female participants were divided into two subgroups based on age: those aged ≥55 years and those <55 years.This division was based on the fact that women aged <55 years exhibited significantly higher odds of depression (AOR=1.75;95% CI: 1.23-2.48).Although female   4).

DISCUSSION
We investigated the impact of tobacco smoking on depression by analyzing data retrieved from the TWB.Several noteworthy findings were obtained.First, we revealed that participants who smoked tobacco exhibited higher odds of depression than those who did not.Furthermore, we conducted sexspecific analyses and found that female participants who smoked tobacco had significantly higher odds of reporting depression than those who did not.Finally, a subgroup analysis of age-stratified groups of female participants revealed that younger women with a tobacco smoking habit exhibited higher odds of depression than older women.The correlation between tobacco use and depression was established in a previous study 22 .The present study further confirmed this relationship.Additionally, compared with men, women exhibited higher odds of reporting depression.Therefore, in subsequent analyses, we evaluated the differences in the outcomes between men and women.We found that men who smoked tobacco did not exhibit significantly higher odds of reporting depression than women smokers.This finding may be attributed to the fact that the prevalence rate of tobacco smoking among the male participants was >60%, whereas that among female participants was <7% in our study.Notably, despite this disparity, our findings indicate a substantial association between tobacco smoking and depression among female participants.This finding is noteworthy considering the increasing prevalence of tobacco smoking among young women in recent years compared with older women 9 .A study demonstrated that tobacco smoking increased the risk of depression in women, with this trend more commonly observed in pre-menopausal than in post-menopausal women 23 .Furthermore, the younger women in our study, but not the older women, exhibited higher odds of reporting depression, although menopause was not identified as a significant factor for depression.This may be because of the complex interplay between the post-menopausal and aging effects on depression.
Covariates other than tobacco smoking were adjusted for in the statistical analysis.Among these covariates, regular exercise and good sleep quality emerged as protective factors in our study, which is in agreement with the results of previous studies.Regular physical exercise was identified as a protective factor and was found to reduce the prevalence of depression and potentially mitigate its symptoms 24 .In our study, the protective effect of regular exercise on depression was also significant across sex-stratified groups.Furthermore, in previous studies, poor sleep quality was associated with an increase in the OR for depression and other mental disorders.Moreover, in the present study, good sleep quality served as the protective factor against depression.A family history of depression was identified as a risk factor for depression in previous studies 18 , and the same result was observed for all the participants of the present study.Notably, in the present study, a family history of depression significantly increased the risk of depression in older women, but not in younger women.Additionally, older women who consumed alcohol exhibited significantly higher risk of depression.The same connection between alcohol use and family history of depression was noted in women in previous studies 25 .However, this phenomenon was only apparent in older women in the present study because the effect of tobacco smoking on depression was more pronounced in younger women than in older women 25 .
A potential link between tobacco smoking or alcohol use and depression has been suspected 26 .A prevailing hypothesis is the stress-coping model, which posits that individuals who experience higher levels of stress are more prone to resort to the use of tobacco, alcohol or other substances as a means of emotional regulation 27 .Older women were reported to consume alcohol to regulate emotions, especially after menopause 28 .In our study, we observed varying impacts of tobacco and alcohol use on the risk of depression among women across different age groups.This phenomenon could be indicative of the increased prevalence of tobacco smoking among young women in recent years.

Limitations
This study has some limitations that must be acknowledged.First, we used PHQ-4 for evaluating depression among the participants of our study.However, PHQ-4 is a measure of merely the presence of depression symptoms and cannot be used to arrive at clinical diagnoses.Therefore, clinical confirmation through in-depth assessment is necessary to establish a definitive diagnosis of depression.Second, we only recruited participants aged >40 years from the TWB.Moreover, considering the recent shift in tobacco smoking trends, particularly among young adults, the study may not fully reflect the conditions and trends among young adults in Taiwan 29 .Third, this is a cross-sectional study which is not able to make causal inference between tobacco and depression.Forth, the exclusive use of TWB participants in the present study limits generalizability to other countries.

CONCLUSIONS
This study provided valuable insights into the relationship between tobacco smoking and the odds of reported depression.A notable association was observed between habitual tobacco use and a high risk of depression.However, women, particularly younger women, had high odds of reporting depression.The prevalence rates of tobacco smoking tend to be considerably higher in men than in women.However, these differences between women and men have been decreasing over time 6 .Moreover, the prevalence of tobacco smoking has been increasing among younger women than among older women in recent years 30 .Given the increased risk of depression associated with tobacco smoking, especially among younger women, efforts should be taken to promote the cessation of tobacco smoking.

Table 4 .
Associations of smoking behaviors and depression among the female population, stratified by age, in participants aged 40-70 years, 2015-2020 (N=17949)